The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics
The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics
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DOI：
10.1093/hmg/ddv135
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发表时间：
2015-07-15
影响因子：
3.5
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Fontaine, Sarah N.;Martin, Mackenzie D.;Dickey, Chad A.
tau 蛋白是一种神经元微管 (MT) 相关蛋白，具有维持 MT 稳定性的作用，异常过度磷酸化和聚集的 tau 蛋白的病理性积累与许多遗传性和散发性神经退行性疾病有关，包括额颞叶痴呆和阿尔茨海默病。以 tau 蛋白为靶点治疗这些疾病是一个引起人们强烈兴趣的领域，为此，细胞分子伴侣的调节是一个潜在的治疗靶点。特别是，组成型 Hsp70 同工型 Hsc70 似乎与 tau 高度相关，保持 tau 蛋白水平并与其协同组装 MT。但 tau 和 Hsc70 之间的关系，以及这种相互作用对神经元的影响及其治疗意义仍然未知。使用人类显性失活 Hsc70（类似于这一重要伴侣的异构体选择性抑制），我们首次发现 Hsc70 活性需要刺激细胞和大脑中的 MT 组装。然而，令人惊讶的是，活跃的 Hsc70 也需要活跃的 tau 来调节体内 MT 组装，这表明 tau 在某些方面充当 Hsc70 的共伴侣来协调 MT 组装。尽管通过生化测定，tau 蛋白与作为底物的 Hsc70 结合，但仍然如此。此外，我们发现，虽然慢性 Hsc70 抑制会损害 MT 动力学，但小分子 Hsp70 抑制剂的间歇治疗可降低脑组织中的 tau 蛋白，而不会破坏 MT 完整性。因此，在 tau 蛋白病中，MT 损伤会对神经元造成损害，可以利用 tau 蛋白与 Hsc70 机制的独特关系来消耗 tau 蛋白水平，而不损害 MT 网络。
The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.